HOW ARE POTENT BULKY CARCINOGENS ABLE TO INDUCE SUCH A DIVERSE ARRAY OF MUTATIONS

Mutations induced by activated benzo[a]pyrene ((+)-anti-B[a]PDE) in Es cherichia coil are being investigated, by using both random and adduct -site-specific mutagenesis approaches. A working hypothesis was propos ed that the major adduct of (+)-anti-B[a]PDE (formed at N-2-Gua) is ab le to induce different base-substitution mutations (e.g., GC-->TA vs, GC-->AT) depending upon its conformation in DNA, which can be influenc ed by various factors, notably DNA sequence context. Frameshift mutati ons are also common with (+)-anti-B[a]PDE, and other work suggested th at the frameshift and base-substitution mutagenesis pathways are coupl ed. The simplest hypothesis to rationalize this interrelationship is t hat a single (+)-anti-B[a]PDE adduct in a single conformation can be b ypassed via either a frameshift or a base-substitution pathway. This c ounterintuitive notion can be reconciled if there are two different ki nds of conformations on the pathway to mutagenesis: a class I conforma tion, which is the initial conformation of a DNA adduct in double-stra nded DNA before its encounter with a DNA polymerase, and a class ii co nformation, which is the conformation that forms at a single-strand/do uble-strand DNA junction during replication by a DNA polymerase. Thus, GC-->TA and GC-->AT mutations may be induced by different class I con formations, whereas base substitution and frameshift mutations may be induced by the same class I conformation but by different class II con formations. The pathway of mutagenesis would be dictated by the releva nt class I and II conformations, which in turn would be controlled by various factors, notably DNA sequence context. (C) 1995 Wiley-Liss, In c.